Abstract
BackgroundMultiple cellular functions are compromised in amyotrophic lateral sclerosis (ALS). In familial ALS (FALS) with Cu/Zn superoxide dismutase (SOD1) mutations, the mechanisms by which the mutation in SOD1 leads to such a wide range of abnormalities remains elusive.Methodology/Principal FindingsTo investigate underlying cellular conditions caused by the SOD1 mutation, we explored mutant SOD1-interacting proteins in the spinal cord of symptomatic transgenic mice expressing a mutant SOD1, SOD1Leu126delTT with a FLAG sequence (DF mice). This gene product is structurally unable to form a functional homodimer. Tissues were obtained from both DF mice and disease-free mice expressing wild-type with FLAG SOD1 (WF mice). Both FLAG-tagged SOD1 and cross-linking proteins were enriched and subjected to a shotgun proteomic analysis. We identified 34 proteins (or protein subunits) in DF preparations, while in WF preparations, interactions were detected with only 4 proteins.Conclusions/SignificanceThese results indicate that disease-causing mutant SOD1 likely leads to inadequate protein-protein interactions. This could be an early and crucial process in the pathogenesis of FALS.
Highlights
Amyotrophic lateral sclerosis (ALS), a progressive and fatal disorder of the central nervous system (CNS), selectively affects both upper and lower motor neurons in the cerebral cortex, brain stem and spinal cord
10 percent of amyotrophic lateral sclerosis (ALS) cases are of the hereditary type, and about 20% of familial ALS (FALS) cases are associated with Cu/Zn superoxide dismutase (SOD1) mutations [1,2]
In symptomatic DF mice aged 145 days, 34 proteins were unambiguously identified by the analysis (Table 1). These proteins could be grouped into 7 approximate functional categories: heat shock proteins (HSPs) and protein degradation; ATPases; glycogenolysis, glycolysis and TCA cycle; cytoskeleton and structure; membrane and protein trafficking; protein biosynthesis; and others (Table 1)
Summary
Amyotrophic lateral sclerosis (ALS), a progressive and fatal disorder of the central nervous system (CNS), selectively affects both upper and lower motor neurons in the cerebral cortex, brain stem and spinal cord. The second hypothesis, the ‘‘oxidative damage’’ theory, conjectures that toxicity is caused by the aberrant chemistry of the metal-binding sites of the mutant SOD1, such as peroxidase or superoxide-reducing activities and peroxynitrite catalysis. These hypotheses, are unable to explain the multiple perturbations of cellular function identified in FALS, including excessive excitatory toxicity, protein misfolding, impaired energy production, abnormal calcium metabolism, altered axonal transport, activation of proteases and nucleases, and so on [1,2]. In familial ALS (FALS) with Cu/Zn superoxide dismutase (SOD1) mutations, the mechanisms by which the mutation in SOD1 leads to such a wide range of abnormalities remains elusive
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